AML with t821q22q22AML7 RUNX1ETOCBFA2T1

This type of CBF AML is associated with t(8;21) and its relatively rare variants, such as insertions ins(8;21) (q22;q22q22) or ins(21;8)(q22;q22q22), and complex translocations involving three or four different chromosomes that invariably include chromosomes 8 and 21 with breaks in bands 8q22 and 21q22. The t(8;21) represents one of the most frequent chromosomal aberrations in AML, occurring in approximately 6% of adult and 12% of childhood patients.13 Interestingly, most patients, approximately 70%, carry at least one additional (secondary) chromosome abnormality, the most frequent of which are loss of one sex chromosome (-Y in male and -X in female patients), del(9q), and trisomy of chromosome 8 (+8).23'24

Both t(8;21) and its variants lead to fusion of the DNA-binding domain of the RUNX1 gene, located at 21q22, with the CBFA2T1 gene at 8q22 and creation of a chimeric gene RUNX1-CBFA2T1. The chimeric fusion protein impairs normal hematopoiesis through a dominant-negative inhibition of the wild-type RUNX1. In addition, it has been shown that RUNX1-CBFA2T1 itself recruits nuclear corepressor complexes, which includes the histone deacetylase enzyme HDAC1, and is responsible for transcriptional repression of RUNX1 target genes, and thus generates novel signals that alter normal transcription. These observations have prompted studies attempting to reverse the block of differentiation using histone deacetylase (HDAC) inhibitors.25

Morphologically, the presence of t(8;21)/RUNX1-CBFA2T1 is strongly (but not exclusively) associated with AML with maturation in the neutrophil lineage. Characteristic pink-colored cytoplasm of neutrophils and an increased number of eosinophil precursors [without abnormalities typical for AML with inv(16)] appear to distinguish patients with t(8;21) from other patients with AML with maturation but without t(8;21)/RUNX1-CBFA2T1.26'27

Notably, the clinical outcome of patients with t(8;21) is relatively favorable,8-10,12-14 especially when regimens containing repetitive cycles of high-dose cytarabine are used as postremission therapy.28,29 The favorable outcome does not seem to be influenced by the presence of secondary chromosome aberrations, although one recent study reported loss of the Y chromosome in male patients to be associated with shorter overall survival,23 but this has not been corroborated by another large study.24

AML with inv(16Xp13p22y CBFB-MVH7 7

This type of CBF AML is characterized by the presence of inversion of chromosome 16, inv(16)(p13q22), or, less commonly, a reciprocal translocation between homologous chromosomes 16, t(16;16)(p13;q22), in leukemic blasts. These chromosome aberrations can be detected in about 7% of adult and 6% of pediatric AML patients.10,13 Notably, secondary aberrations [e.g., +22, +8, del(7q), or +21] are less common in patients with inv(16)/t(16;16) than in patients with t(8;21), being detected in approximately one-third of patients with inv(16)/t(16;16).23,24

Both the inv(16) and the t(16;16) fuse the myosin, heavy chain 11, smooth muscle gene (MYH11) with the C terminus of the CBFB gene. The chimeric protein retains the ability to interact with the RUNX1 and has been suggested to block CBF-dependent transcription.22 The marrow of patients with inv(16)/t(16;16)/CBFB-MYH11 shows monocytic and granulocytic differentiation and abnormal eosinophils, a hallmark of this disease. These eosinophils are essentially always present, albeit sometimes scarce, constituting as little as 0.2% of marrow cells.

The prognosis of CBF AML patients with inv(16)/t(16;16) is favorable,8-14 and can be improved by regimens with multicourse high-dose cytarabine.30 Two large recent studies demonstrated that patients who carry a secondary +22 in addition to inv(16) or t(16;16) have a significantly reduced risk of relapse compared with patients with an isolated inv(16)/ t(16;16).23,24 The reasons for this difference in outcome and the molecular consequences of trisomy 22 remain to be elucidated.


Acute promyelocytic leukemia (APL) is the third category in the WHO classification that is characterized by specific cytogenetic and molecular genetic rearrangements as well as unique marrow morphology, presenting clinical features, and responsiveness to targeted therapy with all-trans-retinoic acid (ATRA). APL comprises from 8% (adults) to 10% (children) of AML cases.13 Essentially, all patients with APL carry a gene fusion of the retinoic acid receptor a (RARA) gene, located at 17q12-21, with one of several partner genes, the most common of which is the promyelocytic leukemia (PML) gene, mapped to 15q22. In the vast majority (>90%) of APL patients, the PML-RARA fusion gene is created by a subtle but detectable microscopically reciprocal translocation t(15;17)(q22;q12-21); in an additional 4%, the PML-RARA gene is generated by an insertion of a small segment from 17q, with the RARA gene into the locus of the PML gene.31 Most of these insertions are cryptic, i.e., not detectable by routine cytogenetic study, and associated with a normal karyotype; they can be identified only using RT-PCR or fluorescence in situ hybridization (FISH). Approximately one-third of APL patients with t(15;17) carry at least one secondary aberration, the most common of which is trisomy 8 or 8q. Additionally, in a small proportion of APL cases, other, rather infrequent, chromosomal aberrations are found, including t(11;17)(q23;q12-21), t(11;17)(q13;q12-21), t(5;17) (q35;q12-21), and dup(17)(q21.3q23). Each of these rearrangements results in a fusion of the RARA gene with, respectively, the PLZF gene at 11q23, NUMA1 gene at 11q13, NPM gene at 5q35, and STAT5b gene at 17q21.1-21.2.32,33

The RARA gene is a member of the nuclear hormone receptor gene family and contains transactivation, DNA-binding, and ligand-binding domains. As a consequence of the t(15;17) or ins(15;17), the DNA- and lig-and-binding domains of RARA are fused to the PML gene. The chimeric PML-RARA fusion protein binds to corepressor/HDAC complexes with higher affinity than does the wild-type RARA, leading to aberrant chro-matin acetylation and alterations of chromatin conformation that inhibit the normal transcription of genes regulated by RARA. This blocks cell differentiation and leads to the accumulation of leukemic blasts at the promyelocytic stage. Importantly, therapeutic doses of ATRA, but not physiological ATRA levels, are capable of changing conformation of the PML-RARA protein and releasing corepressor/HDAC complexes that lead to transcriptional activation of downstream target genes. Moreover, both ATRA and arsenic trioxide, another compound used in targeted APL treatment, also induce proteolysis of the PML-RARA protein. This leads to granulocytic differentiation of the leukemic blasts.34

A strong correlation exists between t(15;17)/PML-RARA and its variants and marrow morphology in which abnormal promyelocytes dominate. There are two major morphologic subtypes of APL, hypergranu-lar (or typical) and microgranular (or hypogranular), and both are associated with the presence of t(15;17)/PML-RARA or variants. The microgranular variant, which sometimes can be misdiagnosed morphologically as acute monocytic leukemia, is associated with very high leukocyte counts with abundant abnormal microgranular promyelocytes.1

It is important to determine which of the APL-associ-ated translocations and gene fusions are present, because patients with t(11;17)(q23;q12-21)/PLZF-RARA are resistant to standard ATRA-based therapy. Although it has been reported that t(11;17)(q23;q12-21)/PLZF-RARA-positive APL displays distinguishing morphological and immunophenotypic characteristics, such as prevalence of blasts with regular nuclei, an increased number of Pelger-like cells, and CD56 positivity,35 the diagnosis should always be supported by results of cytogenetic, FISH, and/or RT-PCR analyses.

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